PATHOLOGY & ONCOLOGY RESEARCHVol. 4 No. 3, 1998

 Article

BMD188, A Novel Hydroxamic Acid Compound, Demonstrates Potent Anti-Prostate Cancer Effects in vitro and in vivo by Inducing Apoptosis: Requirements for Mitochondria, Reactive Oxygen Species, and Proteases

Dean G TANG1, Li LI1, Zhenyu ZHU1, Bindu JOSHI1, Carl R JOHNSON4, Lawrence J MARNETT5, Kenneth V HONN2, John D CRISSMAN6, Stanislaw KRAJEWSKI7, John C REED7, József TÍMÁR8, Arthur T PORTER3

1Biomide Laboratories, Wayne State University, Detroit, USA
2Department of Radiation Oncology, Wayne State University, Detroit, USA
3Karmanos Cancer Insitute, Detroit, USA
4Department of Chemistry, Wayne State University, Detroit, USA
5Department of Biochemistry, Vanderbilt University Medical Center, Nashville, USA
6Department of Pathology, Wayne State University, Detroit, USA
7Apoptosis & Cell Death Program, The Burham Institute, La Jolla, USA
81st Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, Hungary

 

A newly synthesized cyclic hydroxamic acid compound, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was found to induce the apoptotic death of cultured prostate cancer cells by activating caspase-3. Orally administered BMD188 significantly inhibited the primary growth of prostate cancer cells (Du145) orthotopically implanted into SCID mice. Mechanistic studies indicated that BMD188 did not alter the protein levels of several Bcl-2 family members. In contrast, the BMD188 effect required three essential factors: reactive oxygen species (ROS), the mitochondrial respiratory chain function, and proteases. First, the apoptosis-inducing effect of BMD188 could be blocked by ROS scavengers such as Desferal. Second, both BMD188-induced PARP cleavage as well as PC3 cell apoptosis could be dramatically inhibited by several complex-specific mitochondrial respiration blockers. The involvement of mitochondria was also supported by the observations that BMD188 dramatically altered the mitochondrial distribution and morphology without affecting the cellular ATP levels. Finally, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors (TPCK and TLCK) as well as by caspase inhibitors (zVAD-fmk and DEVD-CHO). Collectively, the present study suggests that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells. Pathology & Oncology Research, Vol 4, Nr 3, 179-190, 1998

Key words: hydroxamic acid; prostate cancer; apoptosis; free radical; mitochondria; chemotherapy


Received: May 26, 1998; accepted: Aug 18, 1998
Correspondence: Dean G TANG, Department of Radiation Oncology, Wayne State University, 407 Life Science Bldg. Detroit 48202, USA; Tel: (313)5772184, Fax: (313)5772375; E-mail: dtang@sun.science.wayne.edu

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